1240
H.-O. Kima, M. Kahn
LETTER
Nakanishi, H.; Ruan, F.; Cao, B.; Minarik, R.; Little, T.;
Nelson, S.; Nguyen, M.; Gall, A.; Kahn, M. Bioorg. Med.
Chem. Lett 1998, 8, 2321. c). Kim, H. -O.; Kahn, M.
Tetrahedron Lett. 1997, 38, 6483.
(2) Rodriguez, M.; Llinares, M.; Doulut, S.; Heitz, A.; Martinez,
J. Tetrahedron Lett. 1991, 32, 923.
(3) Typical Experiment of 2:2a: To a stirred solution of Boc-
Lys(Cbz)-OH (1.9 g, 5 mmol) in THF (10 mL) was added CDI
(810 mg, 5 mmol) at r.t. After 10 min, to this stirred solution
was added a solution of NaBH4 (300 mg, 8 mmol) in H2O (5
mL) in one portion at r.t. The resulting solution was then
stirred at rt for 12 h. After dilution with EtOAc (100 mL), the
solution was washed with 1N HCl (60 mL), sat. NaHCO3 (60
mL), brine (60 mL), dried (MgSO4), passed through a short
pad of SiO2, and concentrated to provide a white solid (1.94g,
100%). 1H NMR (500 MHz, CDCl3) d 1.43 (s and m, 15H),
3.20 (m, 2H), 3.60 (m, 3H), 4.80 (m, 2H), 5.15 (s, 2H), 7.35
(m, 5H). mp 65-68 °C (Lit.2 64-67 °C). The product was pure
enough for the next reaction without further purification.
(4) Typical Experiment for 3:3a: A mixture of
COOEt
Me
S
BocHN
PPh3, DEAD,
THF
N
Boc
COOEt
N
S
+
2a
(5)
BocHN
N
Me
94%
ethylbromopyruvate (1.4 mL of 90% pure, 10 mmol) with
thiourea (760 mg, 10 mmol) in EtOH (20 mL) was heated at
reflux for 12h. Concentration gave a white solid in
quantitative yield. 1H NMR (500 MHz, CD3OD) d 1.39 (t, 3H,
J = 7.5Hz), 4.40 (q, 2H, J = 7Hz), 7.71 (s, 1H). MS (ES) m/z
173.1 (M+H+). This solid was neutralized by sat. NaHCO3 and
extracted with EtOAc for the use for the next reaction. To a
stirred solution of above aminothiazole ester (350 mg, 2
mmol) in THF (10 mL) was added Boc2O (440 mg, 2 mmol),
followed by TEA (0.6 mL, 4 mmol) and DMAP (20 mg) at rt.
After stirring at rt for 12 h, the solution was diluted with
EtOAc (50 mL), washed with 1 N HCl (50 mL), dried
(MgSO4), passed through a short pad of SiO2, and
NHCbz
1i
3d
With the dipeptide isostere 1a in hand, we synthesized tet-
rapeptidyl thiazole 4 based upon the sequence of the sub-
strate D-Phe-Pro-Arg. Treatment of 1a with TFA,
followed by coupling with Boc-D-Phe-Pro-OH in the
presence of EDCI/HOBt and subsequent deprotection of
the Boc and Cbz groups afforded 4 in 61% yield (Eq. 6).
concentrated to provide a yellow foamy solid (460 mg, 85%).
1H NMR (500 MHz, CDCl3) d 1.33 (t, 3H, J = 7Hz), 1.53 (s,
9H), 4.38 (q, 2H, J = 7Hz), 7.78 (s, 1H), 8.5 (br, 1H): MS (ES)
m/z 273 (M+H+).
S
D-Phe-Pro-NH
1. TFA
N
H
COOEt
(6)
N
2. Boc-D-Phe-Pro-OH,
EDCI, HOBt, THF
(5) Connell, R. D.; Rein, T.; Akermark, B.; Helquist, P. J. Org.
Chem. 1988, 53, 3845.
(6) Abarghaz, M.; Kerbal, A.; Bourguignon, J.-J. Tetrahedron
Lett. 1995, 36, 6463.
1a
3. TFA, thioanisole
61%
NH2
4
(7) Typical Experiment of 1:1a: To a stirred solution of lysinol 2a
(39 mg, 0.1 mmol) and 3a (27 mg, 0.1 mmol) in THF (2 mL)
was added PPh3 (40 mg, 0.15 mmol), followed by DEAD (25
mL, 0.15 mmol) at rt. After 30 min, additional PPh3 (10 mg)
and DEAD (7 mL) were added to the solution. After 30 min,
the solution was concentrated to give an oil which was
purified by preparative TLC (hexane: EtOAc = 80:20 to
70:30) to provide a sticky oil (51 mg, 82%). 1H NMR (500
MHz, CDCl3) d 1.28 (s, 9H), 1.34 (t, 3H, J = 7Hz), 1.50 (m,
6H), 1.59 (s, 9H), 3.21 (m, 2H), 4.11 (m, 3H), 4.32 (q, 2H,
J = 7Hz), 5.07 (s and br, 3H), 7.33 (m, 5H), 7.75 (s, 1H):
(CD3OD) d 1.24 (s, 9H), 1.37 (t, 3H, J = 7Hz), 1.4-1.6 (m,
6H), 1.61 (s, 9H), 3.14 (t, 2H, J = 7Hz), 4.0 (m, 2H), 4.25 (m,
1H), 4.36 (q, 2H, J = 7Hz), 5.06 (s, 2H), 6.32 (d, 1H,
J = 9.5Hz), 7.34 (m, 5H), 7.92 (s, 1H): MS (ES) m/z 621
(M+H+).
In summary, we have developed a facile synthetic method
for the preparation of azole bearing reduced dipeptides by
the reaction of the aminoazoles with N-protected amino
alcohols in good to excellent chemical yields.
Acknowledgement
The authors thank Dr. Thomas Vaisar for obtaining the mass spec-
tra.
References and Notes
(1) a) Boatman, P. D.; Ogbu, C.; Eguchi, M.; Kim, H.-O.;
Nakanishi, H.; Cao, B.; Shea, J. P.; Kahn, M. J. Med. Chem.
1999, 42, 1367 and references cited therein. b) Ogbu, C.;
Qabar, M.; Boatman, P. D.; Urban, J.; Meara, J.; Ferguson,
M.; Tulinsky, J.; Lum, C.; Babu, S.; Blaskovich, M.;
Article Identifier:
1437-2096,E;1999,0,08,1239,1240,ftx,en;S08499ST.pdf
Synlett 1999, No. 8, 1239–1240 ISSN 0936-5214 © Thieme Stuttgart · New York